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About the Regulatory Profession

The regulatory function is vital in making safe and effective healthcare products available worldwide. Individuals who ensure regulatory compliance and prepare submissions, as well as those whose main job function is clinical affairs or quality assurance are all considered regulatory professionals.

Regulatory Code of Ethics

One of our most valuable contributions to the profession is the Regulatory Code of Ethics. The Code of Ethics provides regulatory professionals with core values that hold them to the highest standards of professional conduct.

Regulatory Competency Framework

Like all professions, regulatory is based on a shared set of competencies. The Regulatory Competency Framework describes the essential elements of what is required of regulatory professionals at four major career and professional levels.

Regulatory Convergence

Join the brightest minds in regulatory at the annual Regulatory Convergence. See the global regulatory community in action. Intensive workshops. Topical sessions. Meet ups with regulators. This is where it all comes together.

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The regulatory function is vital in making safe and effective healthcare products available worldwide. Individuals who ensure regulatory compliance and prepare submissions, as well as those whose main job function is clinical affairs or quality assurance are all considered regulatory professionals.

One of our most valuable contributions to the profession is the Regulatory Code of Ethics. The Code of Ethics provides regulatory professionals with core values that hold them to the highest standards of professional conduct.

Like all professions, regulatory is based on a shared set of competencies. The Regulatory Competency Framework describes the essential elements of what is required of regulatory professionals at four major career and professional levels.

Join the brightest minds in regulatory at the annual Regulatory Convergence. See the global regulatory community in action. Intensive workshops. Topical sessions. Meet ups with regulators. This is where it all comes together.

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Introduction

OTC and Complementary Medicine

Australia has been acknowledged to be the world’s third fastest growing market in self-medication sales.1 Medicines and Medical Devices Regulation (MMDR) introduces a three-tiered, risk-based framework along with permitted indication, efficacy claims, and incentive industry innovation for complementary medicines.2 Some medicines are “registered” while others are “listed,” or “listed assessed” on the Australian Register of Therapeutic Goods (ARTG). According to the 1990 Therapeutic Goods Regulation, complementary medicine consists of one or more designated active ingredients as defined in Schedule 14 of the Regulation with clearly established identity and traditional use.3

Generally, most of the OTC medicines are “registered,” whereas Complementary Medicines (CMs) are “listed.” These medicines are available without a doctor’s prescription.

OTC medicines are mentioned in the Part 3 of Schedule 10 of the 1989 Therapeutic Goods Act.

Figure 1 provides the OTC medicines classification based on point of sale.4,5

Figure 1. OTC Medicines Classification.

OTC medicines registered and certified by the Australian Therapeutic Goods Administration (TGA) have an AUST R number and are evaluated for quality, safety and efficacy. There are five application levels for registering OTC medicines: N1, N2, N3, N4 and N5. Application level selection is dependent on many attributes. These medicines have therapeutic claim for the treatment or prevention of disease and, generally, have an intermediate risk level associated with them. Shelf life for these medicines is determined via stability data; however, in the case of an N2 Application, finished product shelf life, warning and direction for use, should be in line with OTC monograph. Medicines falling under this category could include those for pain relief, cough and cold, and antiseptic creams, etc. Table 1 reflects OTC medicine application classification based on risk level, data requirement, and total evaluation time.6-10

Table 1. OTC Medicine Application Classification.

Application Level

Medicine Type

Risk Level

Attributes

Applicable Data Requirement

Total TGA evaluation Time (Target Working Days)

N1

Generic

Negligible

Clones or flavor/fragrance/color variants of a currently registered medicine

CTD M1

45

N2

Generic

Negligible

In line with OTC monograph

CTD M1, CTD M3

55

N3

Generic

Low

Not an N1, N2 or N4 application

CTD M1 (M2) and CTD M3

150

N4

Generic

Low

Active not previously registered

CTD M1, CTD M2, CTD M3 CTD M4 and CTD M5

170

N5

Non-Generic

Moderate

New chemical entity or combination of active ingredients or new indication or strength or dosage forms or direction for use or patient population

Complementary medicines are medicinal products containing herbs, vitamins, minerals, nutritional supplements, homoeopathic and aromatherapy preparations. These therapeutic products contain, wholly or principally, of one or more of the designated ingredients specified in Schedule 14 of the Therapeutic Goods Regulation.11Figure 2 illustrates how these medicines could be listed or registered.

CMs are low-risk medicines listed on the Australian Register of Therapeutic Goods (ARTG). Ingredients in complementary medicines should be selected from the ARTG database.12 CMs assessed by TGA for efficacy have a AUST L (A) number. This is a new category proposed under MMDR and those not assessed for efficacy must have an AUST L number.13 Sponsor or marketing authorization holder self-certify “AUST L” CMs for quality, safety and efficacy; in the case of AUST L (A) sponsors self-certify only for quality and safety while premarket assessment of efficacy is performed by TGA. CMs claims are for health maintenance, enhancement and dietary deficiency.14 Indication for CMs should be selected from the approved TGA indication database.15 Also, warning/direction for use should comply with ARTG ingredient database or based on scientific evidence.16

Figure 2. Complementary Medicine Listing/Registration.

Postapproval Changes

Registered Medicine

A sponsor may propose changes to an existing registered medicine. In such a case, the sponsor must first check the Change Table detailing the types of changes, including information about status codes and application level to determine whether prior TGA approval is required or not. Table 2 reflects the status code.17,18

Table 2. Status Code.

Status Code

Prior Approval Required

Legal Basis

Approximate Evaluation Time (Working Days)

O

×

9D

submission not required

Safety Related Request (SRR)

√

9D (2)

20 (Removal of an indication, addition of warning or precaution)

Self-Assessable Request (SAR)

√

9D (1) or 9D (3)

20

Notification (N)

√

9D(2C)

auto approval

Approvable Change (A)

√

9D

64 / 120

NEW

√

Section 23

170, new ARTG entry required

ASK

√

for changes not included on change table

Proposed changes to a registered OTC product may be classified under following broad categories19 with five different application levels for filing (Table 3.)20,21

labeling

sponsor changes

formulation changes—active and excipient

quality control changes—finished product and starting material

packaging

manufacturing changes—finished product

Consumer Medicine Information (CMI)

Product Information (PI)

other/miscellaneous

Table 3. Different Application Levels With Risk Level, Impact on Quality, Safety and Efficacy, Data Requirement and Total Evaluation Time.

In 2017, under MMDR, TGA introduced a new notification process for low-risk changes for registered medicine. Under this notification process, the sponsor may submit notification via TGA’s electronic Business Services (eBS) in case of notifiable minor changes not involving any change to existing formulation, ingredients, strength, dosage form, indication, claim or directions for use, while ensuring mandatory conditions are met. Sponsors are required to make legal assurance that all conditions specified for that particular variation are met. Once the fee is paid, acknowledgment is automatically sent and ARTG entry is updated.22

Non-notifiable, minor change variations should be submitted to TGA via the electronic variation form. Some changes may result in a medicine being considered as a separate and different product from currently registered medicine under Section 16(1). As a result, new product details must be entered into ARTG. However, the previous AUST R number could be retained, as per Group Order. This application requires prior approval and has status code A. If more than one change is proposed by the sponsor, the change attracting the highest application level is considered.

If the change proposed by the sponsor is not in the changes table, the sponsor must contact the OTC medicines evaluation department. If it is confirmed that no specific change code could be assigned, TGA may use OT1 (application level C1), OT2 (application level C2), OT3 (application level C3), OT4 (application level C4). A written confirmation will be provided to the sponsor by email to endorse the “other” category change code, which must be included with the application as an attachment to the cover letter.23

Listed Medicines

Changes to listed medicines should be filed via the Electronic Listing Facility version 3 (ELF 3) system.24 If the intended change leads to a separate and distinct finished product, a new AUST L is issued by TGA. On the other hand, if change involves restrictions, conditions and intent to replace the currently supplied product, the application then falls under Grouping category and existing AUST L number is retained. Similarly, in case of a minor change to finished product, details or correction of ARTG record, the AUST L number is retained. Table 4 reflects postapproval change category for listed medicine.25

Goods are intended to replace the currently supplied goods, involves transition phase. Individual products within the group remain separate and distinct products.

An application fee equivalent to a new product is payable.

9D(1)

Correction of ARTG Record

Minor change to a product's details

√

Amendment to the ARTGentry

No application fee

Current listing has omissions or mistakes that were made while listing the product

√

An application fee is payable.

9D(3)

Vary/Variation

Minor change to a product's details

√

Amendment to the ARTG entry

An application fee is payable.

9D(2)

Safety-related variations—like removing an indication or has the effect of adding a warning or precaution

√

Labeling

All medicinal product labels must currently comply with the requirements of Therapeutic Goods Order (TGO) 69 General requirements for labels for medicines. A four-year transition period, commencing August 2016, provides for the implementation of TGO 92 Standard for labels of non-prescription medicines which replace TGO 69. During the transition period, OTC medicines must comply with TGO 69 or TGO 92. As of 1 September 2020, all OTC medicinal products marketed in Australia must comply with TGO 92.

TGO 92 have 3 schedules. Schedule 1 and 2 state listing the substances to be declared on the label and listing internationally aligned medicine ingredient names.27

Non-prescription drug labels are considered a form of advertisement to consumer and therefore, must comply with the requirements of the Therapeutic Goods Advertising Code.

Section 7 of TGO 92 states that labels must be in English, clearly visible, not obscured, text size should be not less than 1.5 mm, be in contrasting colors with the background and have metric units of measurements.28

Labels of medicines are required to have advisory/warning statement. A list of medicine along with advisory statement is provided in Required Advisory Statement for Medicine Labels (RASML). The medicines advisory statement, as mentioned in the therapeutic goods permissible ingredient database, also should be considered.29

Critical Health Information (CHI) for Registered OTC Medicine

In the case of listed non-prescription medicine, CHI is not a mandatory requirement; however, CHI is required for registered non-prescription medicines.

Information for a substance that could cause allergic reaction also should be listed on labels. The CHI information should be presented in following order:

active ingredient

indications

warning

direction for use30

Other information, such as safe storage advice, e.g., KEEP OUT OF REACH OF CHILDREN, or mandatory temperature information, e.g., store below 25°C, tamper proof, names of excipients, sponsor/distributor details, also should be included.31

CHI must be presented in one color black or other dark color against the white or contracting background.,32

For scheduled, non-prescription medicines, a signal heading and cautionary statement must appear alone on the first two lines of the main panel of a label. For example, “KEEP OUT OF REACH OF CHILDREN,” NOT TO BE TAKEN.33

Certain advisory statements are also required to be included on medicine labels if a medicine contains ingredients included in "Medicines Advisory Statements Specification 2017." These advisory statements must comply with RASML No 3 (Schedule 1) until 31 December 2018 and RASML No 4 to be in effect 1 January 2019.34

Tamper-evident packaging, as per code of practice, is a not a mandatory requirement, but is one of the conditions to have membership with industry association. It is anticipated that in the near future the tamper evident feature will become a mandatory requirement and will be included in legislation.

For products in Schedule 3 and Schedule 2, the mandatory requirements include: “Pharmacist only Medicine” and “ Pharmacy Medicine,” respectively.35 In case of herbal preparations, the sponsor must state the herbal ingredient species’ name, plant part and preparation on the label.36 Quantification of the herbal active as “dry” or “fresh weight” of the herbal material from which preparation is derived is required.37 If a medicine contains an active ingredient which is a vitamin, a common name word “Vitamin” should appear.38 For topical application medicines, the active ingredient percentage could be expressed as w/w, w/v, v/v or v/w, as appropriate.39

For registered medicines, Critical Health Information (CHI) in a tabulated format is a requirement set out in schedule 8 of TGO 92.40 The CHI must be presented in only one color, either black or another dark color, on a white or outer contrasting background.41

Labels for listing complementary medicines are not submitted at the time of listing the medicine; however, medicine labels for registered complementary medicine are submitted and evaluated by TGA. A sponsor should ensure the graphic, logo, statement of comparative advertisement and professional recommendations are TGCA-compliant. A negative disclosure statement, such as “gluten-free” or “sugar-free” must be true. Apart from this, label statements such as “new” or “advance” are acceptable for a maximum of 12 months from the date of product launch.42

Stability

Australia lies in climatic zones III and IV. For products which are likely to be unstable, real-time stability data of 12 months at 30°C ± 2° C/65% RH ± 5% RH on three batches, along with six months accelerated data (40°C ± 2° C/75% RH ± 5% RH) is required for product registration. For conventional dosage forms, when the active ingredients are known to be stable, it is acceptable to provide six months of real time and accelerated data on two pilot scale batches. No site-specific stability data is required if adequate comparability between sites with validated process and method transfer can be established.43 Ongoing stability studies should be conducted in accordance with the principles of ICH Q1.44

The sponsor of a complementary medicine product is responsible for determining the shelf life and storage condition. Stability data of a minimum two commercial scale batches as per ICH-recommended stability testing frequency should be ensured. TGA recommends monitoring the stability of all active ingredients with a label claim; however, there are challenges in the case of multi-ingredient products for which a forced degradation approach, such as heat, could be used. Based on the author’s experience with product formulations and their stability, it is possible to group ingredients and selectively monitor for a smaller number of ingredients. Also, TGA recognizes shelf life by using stability data of similar products and considering the technical challenges linked with multi-ingredient, complementary medicines. In the case of an herbal product with no defined active components, it is acceptable to monitor physical changes, such as appearance, disintegration time and chromatographic profile. A 10 percent change to an herbal ingredient which is standardized is considered unacceptable and requires justification.45

The Therapeutic Goods Advertising Code 2018 (2018 Code) was enacted on 29 June 2018. This code will become effective 1 January 2019. Code 2018 amends the code of 2015 for schedule 3 medicines. Advertisers will have choice of using one of two statements:

YOUR PHARMACIST'S ADVICE IS REQUIRED or

ASK YOUR PHARMACIST—THEY MUST DECIDE IF THIS PRODUCT IS RIGHT FOR YOU

Statement two will be acceptable when 2018 code comes into force.46

Advertisements for therapeutic goods in Australia are subject to the requirements of the Therapeutic Goods Act 1989 and Regulations, the Competition and Consumer Act 2010, and Therapeutic Goods Advertising Code.47 Advertisers must ensure compliance with the code currently in force. Advertisers will be given six months, between 1 July 2018 and 1 January 2019, to review their existing and planned advertising for ensuring compliance with advertising code 2018 after 1 January 2019.48

By current legislation, Australian websites promoting the use or supply of therapeutic goods must comply with the Therapeutic Goods Advertising Code (TGAC). This code is consistent with the World Health Organization (WHO): Ethical Criteria for Medicinal Drug Promotion 198849 and requires the submission and approval of advertisements.TGAC specifies mandatory elements, such as brand name, approved/permitted indications, ingredients list and warning and precautionary statements for inclusion in an advertisement. Too, all efficacy/safety claims made for a medicine must be evidence-based.50

Restricted representation, such as a serious indication, cannot be advertised unless prior exemption approval has been obtained.51 Diseases, conditions, ailments and defects for which advertising is restricted will include: cardiovascular diseases, dental and periodontal diseases, diseases of joint, bone, collagen, rheumatic disease, eye or ear disease leading to blindness or deafness.52

Conclusion

With the introduction of reforms in response to MMDR via internal, public and targeted consultation, in the case of registered and listed medicine, TGA is increasing flexibility with regard to registration/listing, premarket approval, evidence of efficacy for CMs and effective regulation for advertising via:

establishing work sharing arrangement with oversea regulators for new chemical entity for provisional approval process

implementation of consolidated lists of approved permitted ingredients and list of permitted indications

implementation of an additional approval pathways for new complementary medicines which includes premarket assessment by TGA for efficacy for listed medicines

introduction of statutory timeframes for the approval of new ingredients and adoption of a risk-based approach for the variation of complementary medicines

use of promotional material to indicate a product has been assessed as efficacious53,54

TGA with above stipulated reforms, also could focus on regulatory compliance by introducing financial penalties, sanctions on the sponsors for noncompliant products in market.55 In the author’s experience, TGA could introduce a system for submission of stability data, unit composition, release and shelf life specification, container closure system specification at the time of listing products on TGA eBS portal and develop system to overcome challenge associated with counterfeit medicines.
With many reforms and the switch over transition periods, “grandfathered” medicines will be finished products in the market and compliant with old and upcoming regulations, which may lead to confusion for patients/consumers. It is recommended that TGA develop a system to foster awareness in consumers and to help them to make informed decisions.

About the Author

Abhishek Tongia, MSc, MBA, DTQM, is currently head of regulatory affairs Global Product Stewardship (GPS) for the Asia, India, Middle East and Africa (AIMEA) region at Procter and Gamble Healthcare, Singapore and has held various positions over the last 18 years in global/regional regulatory affairs with Teva Pharmaceutical, GlaxoSmithKline Consumer Healthcare, Novartis Consumer Healthcare, Ranbaxy Pharmaceutical and Dr. Reddys Pharmaceutical. He earned an MSc (pharmaceutical chemistry) and MBA (marketing) from DAVV University, Indore, India. He can be contacted at abhishektongia@hotmail.com.